Biomedical subjects

M Vassalle

Publications and source records attributed to M Vassalle.

At least 19 recordsLinked to original sources

PubMed1992

Role of intracellular Na+ activity in the negative inotropy of strophanthidin in cardiac Purkinje fibers.

The relation between intracellular sodium activity (aNai) and different phases of strophanthidin inotropy was studied in sheep cardiac Purkinje fibers superfused in vitro. Strophanthidin (1 microM) progressively increases aNai whereas increases and then decreases contractile force, induces contracture ('mechanical toxicity') and arrhythmias ('electrical toxicity'). Contractile force begins to decrease at approximately 11 mM aNai. Force and aNai show a positive correlation during the increasing and a negative correlation during the decreasing phase of strophanthidin inotropy. In high [K]o (8, 12 and 16 mM), strophanthidin increases aNai and force to a smaller peak and fails to induce toxicity. In high [Na]o (+18.5%), strophanthidin increases aNai and force to a larger peak and induces electrical toxicity below and mechanical toxicity above a higher aNai value (approximately 15 mM). In higher [K]o, high [Na]o restores the ability of strophanthidin to induce mechanical toxicity. Thus, mechanical toxicity begins when aNai increases past a critical value and the continuing aNai increase correlates with decrease in contractile force and contracture. The critical value of aNai is modified by Ca load related to changes in membrane potential or to Na electrochemical gradient.

Animals↗

PubMed1992

Pacemaker current, membrane resistance, and K+ in sheep cardiac Purkinje fibres.

OBJECTIVE: The pacemaker current in cardiac Purkinje fibres has been attributed to either a decrease in potassium conductance or an increase in a non-specific (Na-K) conductance. The former mechanism would be associated with an increase in membrane resistance (Rm) and the latter with a decrease in Rm. The aim of this study was to obtain evidence in support of one or other mechanism by measuring Rm during the pacemaker current (Idd) under conditions where there is a small or no extracellular potassium depletion. METHODS: Hearts were obtained from anaesthetised sheep and thin strands of ventricular Purkinje fibres were shortened to less than or equal to 1.6 mm. Purkinje fibres were voltage clamped to potentials positive and negative to the potassium equilibrium potential (EK) using a two microelectrode technique. Small current pulses were superimposed on Idd to measure Rm changes. Procedures were used that decrease either the background potassium current IKl or Idd in order to dissect changes in Rm due to K depletion from those due to Idd. RESULTS: Rm increased during Idd, whether the pacemaker current increased or decreased as a function of time. Increasing [K]o from 2.7 to 5.4 mmol.litre-1 decreased Rm and during hyperpolarising steps increased the instantaneous current but did not change Idd amplitude. In 2.7 mmol.litre-1 K, caesium (Cs, 2 mmol.litre-1) increased the holding current (Ih), had little effect on the instantaneous current, and eliminated Idd and associated Rm changes. In 5.4 and 10.8 mmol.litre-1 K, Cs increased Ih and decreased Idd amplitude and in 10.8 mmol.litre-1 K Cs decreased the instantaneous current on hyperpolarisation. If the current was reversed, Cs decreased but did not abolish it. In normal [K]o, barium (Ba, 0.05-0.5 mmol.litre-1) increased Ih and Rm, reduced the instantaneous current but did not increase Idd amplitude. In high [K]o, Ba instead increased the amplitude and rate of development of Idd. When Cs was applied in the presence of Ba, Idd was reduced or eliminated depending on [K]o. CONCLUSIONS: The changes in membrane resistance during the pacemaker current cannot be accounted for by K depletion and suggest that in the range of diastolic depolarisation the pacemaker current results predominantly from a time dependent decrease in K conductance.

Animals↗

PubMed1992

Arrhythmogenic mechanisms in human atrial and ventricular muscle fibers.

Mechanisms which may lead to cardiac arrhythmias were studied in atrial and ventricular tissues from human hearts. In human atrial fibers, diastolic depolarization (DD) was consistently present, but did not induce spontaneous discharge. Epinephrine enhanced DD, could induce delayed afterdepolarizations (DADs) and (in combination with strophanthidin) trigger repetitive activity. The presence of DD modified the recovery of premature action potentials. Human ventricular fibers did not exhibit DD and were more resistant to Ca overload. It is concluded that in atrial tissues the presence of DD may not induce automatic arrhythmias, but it may influence conduction and re-entry rhythms. Cardioactive drugs may induce DADs and repetitive activity in the atria and less easily in the ventricles. The attainment of a threshold may be facilitated when DADs are superimposed.

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PubMed1991

Mechanisms by which calcium modulates diastolic depolarization in sheep cardiac Purkinje fibers.

The mechanisms by which calcium modulates diastolic depolarization (DD) in sheep cardiac Purkinje fibers were studied in vitro. Increasing [Ca]o from 2.7 mM to 10.8 mM increased both the slope and amplitude of DD, induced oscillatory potentials (V(os)), and prolonged depolarization (V(ex)). The steepening of DD occurred even in the absence of an obvious V(os). The increase in DD amplitude was due both to an increase in the maximum diastolic potential and to a less negative steady-state level. At constant [Ca]o, increasing the driving rate had effects similar to those induced by increasing [Ca]o. The increase in DD slope and amplitude was least at the slowest rates and leveled off at the fastest rates in high [Ca]o. Lowering [Ca]o decreased DD slope and amplitude, but spontaneous activity could be present during interruption of the drive. In slowly driven fibers, increasing [Ca]o to 10.8 mM initially shifted the maximum diastolic potential and steady state DD to more negative values, and subsequently shifted the latter (but not the former) to less negative values. On recovery, a transient depolarization occurred. Quiescent fibers exposed to high [Ca]o also underwent a transient hyperpolarization and a subsequent depolarization, whereas reciprocal effects occurred when [Ca]o was lowered. It is concluded that [Ca]o modulates DD through several different mechanisms and that most (but not all) modifications induced are brought about by changes in [Ca]i.

Animals↗

PubMed1991

Role of membrane potential in Ba2+ induced automaticity in guinea pig cardiac myocytes.

STUDY OBJECTIVE: The aim was to study in isolated myocardial cells the role of membrane potential in barium induced spontaneous activity and the ionic mechanism of the underlying pacemaker current. DESIGN: The membrane potential and resistance of single myocytes were studied at different voltage levels by means of current and voltage clamp steps in the absence and presence of barium (Ba). EXPERIMENTAL MATERIAL: The membrane potentials and currents of single guinea pig ventricular myocytes were recorded by means of an intracellular microelectrode through which current could also be passed. MEASUREMENTS AND MAIN RESULTS: In the presence of Ba (0.1-0.2 mM), stepwise depolarisations induced a transient overshoot and initiated action potentials followed by an undershoot, diastolic depolarisation and spontaneous discharge. During progressive depolarisations, membrane resistance (Rm) increased, decreased transiently at the end of the action potential, and reincreased during diastole. Stepwise repolarisations had opposite effects. Hyperpolarisations reversed diastolic depolarisation and could unmask oscillatory potentials (Vos). Voltage clamp steps to +20 mV were followed by outward tail currents during which Rm increased. Larger or longer depolarisations were followed by larger outward tail currents at resting potential level. The outward tail current reversed at potentials negative to EK. CONCLUSIONS: In the presence of Ba, applied depolarisation facilitates the induction of spontaneous activity through an interplay between voltage dependent and time dependent Ba block and unblock of gK1, voltage dependent increase in Rm, increased potassium driving force, and negative shift in the slow inward current threshold and sometimes Vos. The pacemaker potential underlying spontaneous activity is due to the slow re-establishment of Ba block of IK1 during diastole.

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PubMed1991

On the mechanism by which doxorubicin abolishes the oscillatory events induced by Ca overload in single cardiac myocytes.

The mechanism by which doxorubicin (DOXO) modifies the voltage and current changes induced by Ca overload was investigated in isolated guinea pig ventricular myocytes. In the presence of norepinephrine (NE 0.1 microM), drive induces an oscillatory potential (Vos) superimposed on a prolonged depolarization (Vex): DOXO (10-50 microM) decreases or abolishes Vos but exaggerates Vex. In high [Ca]o (5.4-8.1 mM), drive induces Vos and Vex, and DOXO has the same effects as in NE. Trains of voltage-clamp steps induce Ios and Iex (the currents underlying Vos and Vex, respectively): DOXO decreases or abolishes Ios but increases Iex both in NE and high [Ca]o. DOXO does not decrease the slow inward current Isi. Caffeine (5 mM) abolishes Vos and Ios and increases Vex and Iex (as DOXO does), and adding DOXO slightly increased Vex and Iex. Ni (2 mM) (which blocks Na-Ca exchange) decreases or abolishes DOXO-induced Vex and Iex. In papillary muscles, reduced [Na]o or high [Ca]o increases force, but DOXO has little inotropic effect. Reduced [Na]o and high [Ca]o also increase force less in the presence of DOXO. We conclude that DOXO abolishes Vos and Ios but not by blocking the adrenergic receptor, decreasing Isi, or inhibiting Na-Ca exchange. Instead, DOXO may act by impairing uptake and release of Ca by the sarcoplasmic reticulum membrane.

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PubMed1991

Mechanisms of lidocaine actions on normal and abnormal rhythms in canine cardiac tissues in vivo and in vitro.

1. The actions of lidocaine on cardiac pacemaker rhythms were studied in anaesthetized dogs and in Purkinje fibres from hearts of the same animals. 2. In vivo, lidocaine (1 mg/kg, intravenously) slowed the sino-atrial (SA) node rhythm (-5.0%), and (during vagal stimulation) prolonged ventricular standstill by +25.1% and slowed the idioventricular rhythm (-16.7%). A higher dose (4 mg/kg) had more pronounced effects. 3. Propranolol also slowed sinus (-26.2%) and idioventricular (-27.2%) rhythms, and prolonged ventricular standstill (+36.8%). In the presence of propranolol, the effects of lidocaine on idioventricular rhythm were exaggerated. 4. In Purkinje fibres driven in vitro, lidocaine (10 mumol/L) decreased contractile force (-47.9%) and (during the interruption of drive) prolonged the suppression of (+53.2%) and slowed the escape rhythm (-67.0%). 5. In the presence of lidocaine the threshold potential was shifted to less negative values and diastolic depolarization slope was decreased (-23.6%). 6. Lidocaine slowed spontaneously active Purkinje fibres, abolished early afterdepolarizations in low [K]o and slow responses in high [K]o (by shifting the threshold to less negative values), and antagonized strophanthidin arrhythmias. 7. TTX reduced the hyperpolarization by lidocaine in low [K]o and vice versa. 8. We conclude that lidocaine enhances vagally-induced ventricular standstill by depressing the idioventricular rhythm far more than the sinus rhythm, an action enhanced by beta-blockade. Furthermore, lidocaine depresses normal and different types of abnormal automaticity through direct and indirect effects of the blockade of the fast sodium channel.

Animals↗

PubMed1991

Acetylcholine, Ca2+ overload and oscillatory potentials in isolated ventricular myocytes.

The events caused by overdrive-induced calcium overload were studied in guinea pig isolated ventricular myocytes. Overdrive may induce oscillatory potentials (Vos) and a prolonged depolarization (Vex), as well as the underlying currents (Ios and Iex, respectively). Acetylcholine (ACh) reduced or abolished these events, an action which was blocked by atropine. Norepinephrine exaggerated the effects of overdrive, and ACh markedly antagonized such an enhancement. Caffeine at low concentrations increased both Ios and Iex whereas at high concentrations caffeine abolished Ios but increased Iex. Quinacrine abolished both events. Voltage clamp depolarizing steps abolished Ios (and did not reverse it). Thus, the effects of Ca overload are antagonized by ACh in the absence and presence of sympathetic enhancement. Also, the mechanism underlying Ios appears to involve an electrogenic Ca extrusion and not an increase in a nonspecific conductance.

Acetylcholine↗

PubMed1991

On the mechanism of the positive inotropy of low concentrations of strophanthidin.

The hypothesis that low concentrations of strophanthidin may decrease contractile force (and intracellular sodium activity, aiNa) under normal conditions but might increase force (while still decreasing aiNa) under conditions of increased Ca load was tested in sheep cardiac Purkinje fibers perfused in vitro. Strophanthidin was used at concentrations (7.5-25 nM, "low strophanthidin") that decreased both force and aiNa in different preparations. A marked reduction in flow rate of Tyrode solution ("ischemia") increases aiNa and increases and eventually decreases force: during ischemia, low strophanthidin decreases aiNa but increases force. High [Ca]o (16.2 mM) and norepinephrine (10 nM) increase force and decrease aiNa: in their presence, low strophanthidin decreases aiNa further but increases force. Caffeine (4 mM) decreases force and increases aiNa, and low strophanthidin increases force while having little effect on the increase of aiNa. In ventricular trabeculae, strophanthidin decreases force under basal conditions but increases force during ischemia or Ca overload. Thus, strophanthidin decreases force by lowering aiNa under normal conditions, but it increases force in spite (and perhaps because) of the decrease in aina under conditions of increased calcium load.

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PubMed1991

An analysis of calcium effects on diastolic depolarization in sheep cardiac Purkinje fibers.

The events by which [Ca]O modifies diastolic depolarization (DD) were analyzed in sheep cardiac Purkinje fibers perfused in vitro. Cs (2 mM) reduced diastolic depolarization (DD) at different [Ca]O and in 10.8 mM [Ca]O revealed an oscillatory potential (VOS) and the decay of a prolonged depolarization (Vex). In the presence of Cs, procedures that reduce Cai (a slower driving rate, lower [Ca]O or tetrodotoxin) abolished VOS and Vex and partially restored DD. In 10.8 mM [Ca]O and at all driving rates, Cs reduced DD slope, DD amplitude and VOS amplitude but had little effect on the VOS time to peak. In 10.8 mM [Ca]O, decreasing calcium overload by different means (2.6 microM TTX, 0.2 mM Cd) abolished VOS and decreased DD slope and amplitude. Substituting Na with Li induced marked aftercontractions but small VOS. In 10.8 mM [Ca]O, Li increased the amplitude of the aftercontractions and decreased that of VOS. Li also depolarized slightly the resting membrane and abolished the voltage undershoot (Emax) at the end of the action potential. In low [K]O, Li repolarized the resting membrane but the repolarization was maintained only in the presence of Ca. It is concluded that Ca overload causes both VOS and Vex which can either be masked by or can mask DD depending on the magnitude of DD and of Ca overload. VOS is apparently caused by an electrogenic Na-Ca exchange since Li-induced Ca overload increases the aftercontraction but decreases VOS.

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PubMed1990

On the mechanism of overdrive suppression in the guinea pig sinoatrial node.

Factors underlying overdrive suppression were studied in guinea pig sinoatrial node perfused in vitro. Overdrive (1) is followed by a short suppression and a transient decrease in maximum diastolic potential (Emax); (2) causes an immediate decrease and then a reincrease in force followed after overdrive by a transient overshoot; (3) may induce a marked suppression in high [Ca]0, which is a function of the rate and duration of overdrive and is not affected by tetrodotoxin or atropine; (4) in the presence of acetylcholine (ACh), decreases Emax and causes a longer suppression, which may be associated to a transient hyperpolarization; (5) can be initiated periodically by spontaneous beats and the cycles are abolished by calcium antagonists but not by atropine; (6) in high [Ca]0 (but not in ACh) is followed by an oscillatory potential, the amplitude of which depends of the characteristics of overdrive; (7) does not cause suppression in zero [Ca]0; (8) may cause suppression that is due to failure of conduction; and (9) may be followed by a prolonged transient hyperpolarization in the presence of ACh and Cs. Thus, the sinoatrial node, intracellular calcium accumulation enhances overdrive suppression and causes periodic suppression of spontaneous cyclic rhythms. These calcium actions are direct and not related to a potentiation of ACh effects. The elimination of diastolic depolarization by ACh and Cs reveals an overdrive-induced hyperpolarization possibly related to an electrogenic Na extrusion.

Acetylcholine↗

PubMed1990

Strontium induces oscillatory potentials in sheep cardiac Purkinje fibers.

The induction of strontium overload and its electromechanical manifestations, the factors influencing and the mechanism underlying Sr overload were studied in Purkinje fibers perfused in vitro. Strontium: (1) can induce an oscillatory potential (Vos) and repetitive spontaneous activity at low concentrations (1.35-2.7 mM); (2) at high concentrations (5.4-10.8 mM) less frequently causes a Vos but during recovery in Tyrode solution Vos appears as Sr overload recedes; (3) decreases the maximum diastolic potential by inducing a prolonged depolarization (Vex) which subsides slowly during an interruption of drive; (4) induces a larger Vex after procedures that increase Sr loading (fast driving rates, higher [Sr]o or longer action potentials); (5) does not induce Vos and Vex when the slow channel is blocked; (6) exaggerates Vex (but not Vos) in calcium overloaded fibers; (7) exchanges with Na since in low [Na]o the twitch amplitude increases; (8) is removed from the cell at the resting potential since after a period of quiescence the first resumed twitch decreases as a function of the preceding pause duration; (9) needs Na as charge carrier since the slope of diastolic depolarization decreases in low [Na]o. Thus, Sr causes overload even at low concentrations and induces an oscillatory potential and the prolonged depolarization Vex, whose mechanism appears to be an electrogenic Sr extrusion through Na-Sr exchange.

Action Potentials↗

PubMed1990

Effects of strophanthidin on the slow inward current in guinea-pig isolated ventricular myocytes.

1. The effect of strophanthidin on the slow inward current (Isi) and on contractile force were studied in guinea-pig isolated ventricular myocytes and intact papillary muscles, respectively. In myocytes, both low (10 nmol/L) and high (1-10 mumols/L) concentrations had small or no effects in either direction on Isi whereas norepinephrine (10-100 nmol/L) increased it. To determine whether the same results are obtained after decreasing or increasing intracellular calcium or sodium, the same concentrations of strophanthidin were tested in different procedures that are known to (i) increase [Ca]i and decrease [Na]i (high [Ca]o, 3.6-5.4 mmol/L; low [Na]o, 112 mmol/L; (ii) decrease [Ca]i and increase [Na]i (low [Ca]o, 0.45-1 mmol/L; Sr, 1 mmol/L; (iii) decrease [Ca]i and [Na]i (Cd, 0.1-0.2 mmol/L); and (iv) increase [Ca]i and [Na]i (veratridine, 0.2 mumol/L). High [Ca]o and veratridine increased whereas low [Ca]o and Cd decreased Isi. In contrast, during these various procedures, strophanthidin had small and inconsistent effects at a low or high concentration. In intact papillary muscles, low strophanthidin decreased whereas high strophanthidin increased contractile force. It is concluded that strophanthidin has little direct or indirect effect on Isi and that the decrease in force by low and increase in force by high concentrations in intact muscle are probably related to demonstrated decrease and increase, respectively, in intracellular sodium activity.

Action Potentials↗

PubMed1990

The interrelationship of cesium, intracellular sodium activity, and pacemaker potential in cardiac Purkinje fibers.

The actions of cesium (Cs) on intracellular sodium activity (aiNa), membrane potentials, and force were studied in sheep cardiac Purkinje and myocardial fibers superfused in vitro. In Purkinje fibers, Cs (2 mM) decreased diastolic depolarization, aiNa (-6.7%, p less than 0.005), and force (-28.0%, p less than 0.01). The effects of 4 and 8 mM Cs were more pronounced. In quiescent fibers, Cs (2-4 mM) also decreased aiNa (-17.3%, p less than 0.005) and induced an initial hyperpolarization (+5.6 +/- 1.3%, p less than 0.005) followed by a return toward control. Diastolic depolarization was almost abolished by driving the fibers at 180/min (diastole was very short) but still Cs decreased aiNa (-15.4%). Tetrodotoxin decreased aiNa (-16.2%, p less than 0.025) and reduced the Cs-induced fall in aiNa (-2.2%, p less than 0.05). In zero [K]o, Cs decreased aiNa and caused repolarization. In 0.1 mM strophanthidin, Cs did not decrease aiNa any longer and affected the membrane potential little. In quiescent myocardial fibers, Cs (4 mM) decreased aiNa (-12.6%, p less than 0.05) and transiently hyperpolarized (+2.1%). Rubidium (2 mM) decreased aiNa and resting potential in Purkinje fibers and in myocardial fibers and also decreased diastolic depolarization in Purkinje fibers. Thus, cesium and rubidium decrease aiNa and modify the membrane potential but not through a block of the inward pacemaker current If.

Animals↗

PubMed1990

Magnesium and intracellular sodium activity in cardiac Purkinje fibers.

The actions of magnesium on intracellular sodium activity (aiNa), transmembrane potentials and contractile force were studied in sheep cardiac Purkinje fibers perfused in vitro. Increasing [Mg]o from 1.05 to 2-8 mM shortens the action potential, decreases force and increases aiNa in active (and quiescent) fibers. High Ca (8.1 mM) increases force and decreases aiNa: in its presence, 8 mM Mg ('high Mg') decreases force as well as the action potential duration and still increases aiNa. Manganese decreases force and aiNa: the effects of high Mg are not changed by Mn-induced blockade of the slow channel. Even in the presence of 0.25 mM lidocaine (which decreases action potential duration, force and aiNa), high Mg increases aiNa, has little effect on the action potential duration and increases the threshold requirements. In the absence of [Ca]o, 1.35 mM Sr increases the action potential duration as well as aiNa and reduces force: high Mg markedly decreases aiNa, force and action potential duration. Thus, Mg decreases the duration of the action potential (as Ca does) but (in contrast to Ca) decreases contractile force (possibly by acting on intracellular structures) and increases intracellular Na activity. These effects are not dependent on Ca or Na influx and show that the increase in aiNa by Mg is the net result of opposing actions.

Action Potentials↗

PubMed1990

On the mechanism of the different sensitivity of Purkinje and myocardial fibers to strophanthidin.

The mechanism of the different sensitivity of Purkinje and myocardial fibers to strophanthidin was studied in these tissues isolated from the same hearts. Membrane potentials, force and, in some experiments, intracellular sodium activity were recorded under conditions that vary the sodium load in the absence and presence of strophanthidin. Strophanthidin (0.1-0.3 microM) increased force in percent terms more and at a faster rate in Purkinje than in myocardial fibers. Tetrodotoxin (TTX, 2 microM) markedly reduced whereas high [Na]o (176.6 mM) and veratridine (0.2 microM) potentiated strophanthidin inotropy in Purkinje but not in myocardial fibers. The rate of force development was augmented by high [Na]o and veratridine in Purkinje fibers but in myocardial fibers this effect was absent with high [Na]o and smaller with veratridine. Strophanthidin increased the action potential duration at plateau level in Purkinje and decreased it in myocardial fibers. The effects of TTX, high [Na]o and veratridine on the action potential were more pronounced in Purkinje than in myocardial fibers. TTX decreased far more and adding strophanthidin increased intracellular sodium activity (aiNa) less in Purkinje fibers. Strophanthidin increased aiNa to a similar extent in the presence of high [Na]o and veratridine in the two tissues. Thus, changes in Na influx modify the action potential duration, force and strophanthidin inotropy more in Purkinje than in myocardial fibers. This greater sensitivity of Purkinje fibers to strophanthidin does not appear to be related to a larger increase in aiNa, but rather to the changes in action potential (and consequent changes in calcium influx).

Action Potentials↗

PubMed1989

Quinacrine decreases the slow inward current and force in guinea pig ventricular tissue.

In guinea pig isolated ventricular myocytes, quinacrine (40 microM) decreases the action potential amplitude and duration, and markedly decreases the slow inward current (Isi). A lower quinacrine concentration (20 microM) has similar but smaller effects. In guinea pig papillary muscles, quinacrine decreases contractile force reversibly. Thus, in myocardial fibers the decrease in Isi by quinacrine appears to predominate over the inhibition of Na-Ca exchange found in membrane vesicles.

Action Potentials↗

PubMed1989

On the characteristics of the inward tail current induced by calcium overload.

The characterization of an inward tail current (Iex) induced by calcium overload and often associated with the oscillatory current (Ios) was studied by means of a two-microelectrode voltage clamp method in sheep cardiac Purkinje fibers. It was found that: (1) the inward tail current requires a prior depolarization to about -25 mV (or less negative values) in order to appear; (2) after depolarization to those values, the membrane needs to be repolarized to about -45 mV (or to more negative values) for the inward tail current to be initiated; (3) the inward tail current becomes larger after larger or longer clamp steps and increases progressively at more negative potentials; (4) the inward tail current can be separated from other known currents, notably from the pacemaker current; (5) the inward tail current is reduced by quinacrine, a blocker of Na-Ca exchange; (6) the inward tail current does not reverse at less negative potentials; (7) the membrane conductance does not increase during the inward tail current. Thus, the inward tail current shows similarities and dissimilarities with the oscillatory current, probably in relation to a common final pathway and to a different mode of onset of the two currents, respectively.

Animals↗